EpCAM-targeted betulinic acid analogue nanotherapy improves therapeutic efficacy and induces anti-tumorigenic immune response in colorectal cancer tumor microenvironment.

Background: Betulinic acid (BA) has been well investigated for its antiproliferative and mitochondrial pathway-mediated apoptosis-inducing effects on various cancers. However, its poor solubility and off-target activity have limited its utility in clinical trials. Additionally, the immune modulatory role of betulinic acid analogue in the tumor microenvironment (TME) is largely unknown.

A solvent controlled regioselective synthesis of 2- and 4-substituted α-carbolines under palladium catalysis.

A facile method for the chemodivergent synthesis of α-carbolines 1 palladium catalyzed [3+3] annulations of tosyliminoindolines 6 with α, β-unsaturated aldehydes 7 is described. Mechanistically, this cascade reaction proceeds through either a -Michael (in DMF) or -Michael (in NMA) pathway followed by intramolecular cyclization of the intermediate. A preliminary photo-physical study on selected products is also reported.

Iron(III)-Catalyzed Carboannulations of Homopropargylic Alcohols: A One-Pot General Synthesis of 4-(2,2-Diarylvinyl)quinolines and 4-(2,2-Diarylvinyl)-2-chromenes.

A simple and efficient approach for the general synthesis of 4-(2,2-diarylvinyl)quinolines and 4-(2,2-diarylvinyl)-2-chromenes has been developed using Fe(III)-catalyzed intramolecular annulations of homopropargyl substrates and , respectively. The high yields (up to 98%) achieved using simple substrates, an environmentally benign low-cost catalyst, and less hazardous reaction conditions make the methodology inherently attractive.

Substrate-Controlled Product Divergence in Iron(III)-Catalyzed Reactions of Propargylic Alcohols: Easy Access to Spiro-indenyl 1,4-Benzoxazines and 2-(2,2-Diarylvinyl)quinoxalines.

We report herein unprecedented cascade reactions of O-propargyl-N-tosyl-amino phenols with 10 mol% FeCl in DCE at room temperature for 0.67-3 h to form spiro-indenyl 1,4-benzoxazines with 38-89 % yield. Replacing the substrates' oxygen atom by a N-tosylimine group followed by treatment with the same catalyst and solvent at 80 °C produced 2-(2,2-diarylvinyl)quinoxalines in 12-20 h with up to 62 % yield.

Palladium(0)-Catalyzed Heteroannulations of Allenamides: General Synthesis of δ-Carbolines and Benzofuro[3,2-]pyridines.

Palladium(0)-catalyzed reactions between allenamides or and aryl iodides/bromides / provide an easy access to δ-carbolines or benzofuro[3,2-]pyridines . The reaction constitutes a fast intermolecular assembly that takes place in one pot, and the choice of the phosphine ligand is critical for success. A plausible reaction mechanism is proposed.

Palladium-Catalyzed Benzannulations of 1-(Indol-2-yl)but-3-yn-1-ols: Easy Access to Functionalized Carbazoles.

An atom-economical direct synthesis of carbazoles having aryl and aryl ketone groups has been achieved through Pd(II)-catalyzed cascade reactions between 1-(indol-2-yl)but-3-yn-1-ols and aldehydes. The reaction proceeds through alkyne-carbonyl metathesis, an uncommon pathway using palladium catalysts, and constitutes a fast intermolecular assembly through four carbon-carbon bond formations in one pot. Absence of the aldehyde substrate resulted in the formation of C4-aryl-substituted carbazoles.

Palladium(0)-catalysed regioselective cyclisations of 2-amino(tosyl) benzamides/sulphonamides: the stereoselective synthesis of 3-ylidene-[1,4]benzodiazepin-5-ones/benzo[][1,2,5]thiadiazepine-1,1-dioxides.

The Pd(0) catalysed cyclisation reactions between tert-butyl propargyl carbonates and 2-aminotosyl benzamides or sulphonamides deliver 1,4-benzodiazepin-5-ones or sultam derivatives, key components of many biologically active compounds. But 2-amino benzamides/sulphonamides require propargyl carbonates substituted at acetylenic carbon to undergo the reaction resulting in the stereoselective formation of the said products.

Palladium-Catalyzed Synthesis of 1-Vinyltetrahydro-β-carbolines and Aza-spiroindolenines: Access to the Syntheses of 1-Vinyl-β-carbolines and and .

A general synthesis of 1-vinyltetrahydro--carbolines (THBCs) has been achieved via palladium(0)-catalyzed cyclocondensation between allenyltryptamines and aryl iodides. Aza-spiroindolenines could also be accessed from the -unsubstituted indole substrates by simply tweaking the reaction conditions. DDQ-mediated oxidation of THBCs easily afforded -carbolines, which could be synthetically transformed into 1-aroyl--carbolines of pharmacological interest.

Palladium(ii) catalysed cascade strategy for the synthesis of dibenzo[5,6:7,8]cycloocta[1,2-b]indol-10-ols/-10(15H)-ones: easy access to 1,3,5,7-cyclooctatetraenes (COTs).

An atom-economic Pd(ii)-catalysed cascade cyclisation of 2-(biphenylethynyl)anilines tethered to an aldehyde or cyano group leads to the formation of dibenzo[5,6:7,8]cycloocta[1,2-b]indol-10-ols 6 or dibenzo[5,6:7,8]cycloocta[1,2-b]indol-10(15H)-ones 8 with high yields (up to 95%). The reaction proceeds via amino-palladation of the alkyne followed by nucleophilic addition onto the aldehyde/cyano group. Treatment of 6 with p-TsOH·HO smoothly provided cyclooctatetraene (COT) derivatives 7.

Nanoencapsulated betulinic acid analogue distinctively improves colorectal carcinoma in vitro and in vivo.

Betulinic acid, a plant secondary metabolite, has gained significant attention due to its antiproliferative activity over a range of cancer cells. A promising betulinic acid analogue (2c) with better therapeutic efficacy than parent molecule to colon carcinoma cells has been reported. Despite impressive biological applications, low aqueous solubility and bioavailability create difficulties for its therapeutic applications.

Palladium(II)-Catalyzed Cascade Reactions of Ene-Ynes Tethered to Cyano/Aldehyde: Access to Naphtho[1,2-]furans and Benzo[]indoles.

An efficient palladium(II)-catalyzed cascade reaction of ene-yne substrates carrying cyano/aldehyde group is described. It involves successive hetero- and benz-annulations in one pot via -oxo/aminopalladation onto alkyne, followed by 1,2-addition to cyano/aldehyde, providing a convenient synthesis of both naphtho[1,2-]furans and benzo[]indoles. The reaction constitutes a fast intramolecular assembly through several carbon-carbon and carbon-heteroatom bond formations taking place in one pot.

Palladium-catalysed stereoselective synthesis of 4-(diarylmethylidene)-3,4-dihydroisoquinolin-1(2H)-ones: expedient access to 4-substituted isoquinolin-1(2H)-ones and isoquinolines.

An efficient method has been developed for the stereoselective synthesis of 4-(diarylmethylidene)-3,4-dihydroisoquinolin-1(2H)-ones 7 through tandem Heck-Suzuki coupling at rt using easily available substrates. DBU easily converted the exocyclic double bond of these compounds to endo, furnishing 8 and 9. Reduction of the carbonyl group of 7 was smoothly carried out with borane dimethyl sulphide.

One-Pot Access to Benzo[a]carbazoles via Palladium(II)-Catalyzed Hetero- and Carboannulations.

A Pd(II)-catalyzed direct synthesis of benzo[a]carbazoles has been achieved through aminopalladation of alkynes, followed by intramolecular nucleophilic addition of the generated carbon-palladium bond to a tethered cyano/aldehyde group. Compared to literature procedures, this synthetic approach is operationally simple, uses simple substrates, and offers a fast intramolecular assembly resulting in the direct synthesis of benzo[a]carbazoles in which a wide variation of substituents at different sites is well-tolerated, leaving enough opportunity for diversification.

A Palladium-Catalyzed Method for the Synthesis of 2-(α-Styryl)-2,3-dihydroquinazolin-4-ones and 3-(α-Styryl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: Access to 2-(α-Styryl)quinazolin-4(3H)-ones and 3-(α-Styryl)-1,2,4-benzothiadiazine-1,1-dioxides.

An efficient synthesis of 2-(α-styryl)-2,3-dihydroquinazolin-4-ones and 3-(α-styryl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides has been achieved in 39-94% yield through palladium-catalyzed cyclocondensation of aryl/vinyl iodides with allenamides 13-15 and 22, respectively. Base treatment of the N-tosylated products provides an easy access to 2-(α-styryl)quinazolin-4(3H)-ones and 3-(α-styryl)-1,2,4-benzothiadiazine-1,1-dioxides, hitherto unknown heterocycles. The method has been tested with phenyl substituted allenamides, applied for bis-heteroannulation, and used in the preparation of analogues of the natural product Luotonin F.

A potent betulinic acid analogue ascertains an antagonistic mechanism between autophagy and proteasomal degradation pathway in HT-29 cells.

Background: Betulinic acid (BA), a member of pentacyclic triterpenes has shown important biological activities like anti-bacterial, anti-malarial, anti-inflammatory and most interestingly anticancer property. To overcome its poor aqueous solubility and low bioavailability, structural modifications of its functional groups are made to generate novel lead(s) having better efficacy and less toxicity than the parent compound. BA analogue, 2c was found most potent inhibitor of colon cancer cell line, HT-29 cells with IC50 value 14.

Andrographolide Analogue Induces Apoptosis and Autophagy Mediated Cell Death in U937 Cells by Inhibition of PI3K/Akt/mTOR Pathway.

Background: Current chemotherapeutic agents based on apoptosis induction are lacking in desired efficacy. Therefore, there is continuous effort to bring about new dimension in control and gradual eradication of cancer by means of ever evolving therapeutic strategies. Various forms of PCD are being increasingly implicated in anti-cancer therapy and the complex interplay among them is vital for the ultimate fate of proliferating cells.

Synthesis and biological evaluation of a novel betulinic acid derivative as an inducer of apoptosis in human colon carcinoma cells (HT-29).

A novel family of betulinic acid analogues, carrying a triazole unit at C-3 attached through a linker, was synthesized by the application of azide-alkyne "Click reaction". These were screened for their anticancer activity against different cancer cells and normal human PBMC by MTT assay. Compound 2c [(3S)-3-{2-(4-(hydroxymethyl-1H-1,2,3-triazol-1-yl)acetyloxy}-lup-20(29)-en-28-oic acid] was found as the most potent inhibitor of cell line HT-29 with IC50 value 14.

Synthesis and biological evaluation of andrographolide analogues as anti-cancer agents.

A new family of andrographolide analogues were synthesized and screened in vitro against kidney (HEK-293) and breast (MCF-7) cancer cells. The anti-cancer effects of the active analogues (2b, 2c and 4c) were determined by multiple cell based assays such as MTT, immunostaining, FACS, western blotting and transcriptional inhibition of NF-κB activity. Importantly, these compounds were found to possess higher anti-cancer potency than andrographolide and low toxicity to normal (VERO and MCF-10A) cells.

Facile synthesis of 2-arylmethylindoles and 2-vinylic indoles through palladium-catalyzed heteroannulations of 2-(2-propynyl)aniline and 2-(2-propynyl)tosylanilide.

A facile method for the general synthesis of 2-arylmethylindoles has been developed through the reaction of 2-(2-propynyl)aniline or 2-(2-propynyl)tosylanilide with aryl iodides in the presence of Pd(OAc)2, PPh3, and DBU. 2-(2-Propynyl)tosylanilide is found to be reactive also towards electron deficient alkenes in the presence of Pd(OAc)2 and sodium iodide under an oxygen atmosphere, providing easy access to 2-vinylic indoles which possess exclusive E-stereochemistry in the side chain double bond. Operational simplicity, compatibility of the various functional groups, and ease of product formation are the hallmarks of these methods.

Apoptotic and autophagic effects of Sesbania grandiflora flowers in human leukemic cells.

Background: Identification of cytotoxic compounds that induce apoptosis has been the mainstay of anti-cancer therapeutics for several decades. In recent years, focus has shifted to inducing multiple modes of cell death coupled with reduced systemic toxicity. The plant Sesbania grandiflora is widely used in Indian traditional medicine for the treatment of a broad spectrum of diseases.

Palladium-catalyzed approach for the general synthesis of (E)-2-arylmethylidene-N-tosylindolines and (E)-2-arylmethylidene-N-tosyl/nosyltetrahydroquinolines: access to 2-substituted indoles and quinolines.

A facile and efficient method for the synthesis of (E)-2-arylmethylidene-N-tosylindolines and (E)-2-arylmethylidene-N-tosyl/nosyltetrahydroquinoline variants has been developed through palladium-catalyzed cyclocondensation of aryl iodides with readily available 1-(2-tosylaminophenyl)prop-2-yn-1-ols and their higher homologues, respectively. The proposed reaction mechanism invokes the operation of trans-aminopalladation during cyclization (5/6-exo-dig), which ensures exclusive (E)-stereochemistry in the products. The method is fast, operationally simple, totally regio- and stereoselective, and versatile enough to access a variety of 2-substituted indoles and quinolines.

An efficient strategy for the general synthesis of 3-aryl substituted pyrazolo[5,1-c][1,4]benzoxazines and pyrazolo[1,5-a][1,4]benzodiazepin-6(4H)-ones.

An efficient strategy for the general synthesis of 3-aryl substituted pyrazolo[5,1-c][1,4]benzoxazines and pyrazolo[1,5-a][1,4]benzodiazepin-6(4H)-ones has been developed using intramolecular 1,3-dipolar cycloaddition. The hydrazonoyl chloride, the precursor of the cycloadduct, is accessed easily through a two-step reaction carried out in one-pot. It is then used without purification for the base induced formation of the nitrilimine, which undergoes subsequent in situ intramolecular cycloaddition with an alkyne to afford the desired product.

A rapid and facile method for the general synthesis of 3-aryl substituted 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines and their ring fused analogues.

We report a general and facile method that provides rapid entry into 3-aryl substituted 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines and their ring fused analogues in one-pot under palladium-copper catalysis. The methodology utilises simple and easily available substrates of broad range. The applicability of this reaction for the synthesis of optically active products has been demonstrated.

Synthesis, cytotoxicity, and structure-activity relationship (SAR) studies of andrographolide analogues as anti-cancer agent.

A series of analogues of andrographolide, prepared through chemo-selective functionalization at C14 hydroxy, have been evaluated for in vitro cytotoxicities against human leukemic cell lines. Two of the analogues (6a, 9b) exhibited significant potency. Preliminary studies on structure-activity relationship (SAR) revealed that the α-alkylidene-γ-butyrolactone moiety of andrographolide played a major role in the activity profile.

An expedient and facile route for the general synthesis of 3-aryl substituted 1,2,3-triazolo[1,5-a][1,4]benzodiazepin-6-ones and 1,2,3-triazolo[1,5-a][1,5]benzodiazocin-7-ones.

We describe herein a convenient approach for the general synthesis of novel tricyclic scaffolds incorporating a fusion of the 1,2,3-triazole ring with difficultly obtainable medium sized rings such as [1,4]benzodiazepin-5-ones and [1,5]benzodiazocin-6-ones through Sonogashira coupling of an aryl iodide with 2-amino-N-methyl-N-(prop-2-ynyl)benzamide or homologue followed by in situ diazotisation, azidation and cycloaddition reactions. The strategy also allows easy accessibility of the corresponding amide-reduced analogues. The operational simplicity and easy substrate availability make the process cost effective and practical.